Ribonucleotide reductase (RR) is the enzyme responsible for the reductive conversion of ribonucleotides to deoxyribonucleotides. The latter conversion is the rate controlling step in the biosynthesis of deoxyribonucleic acid (DNA), an essential principle for cell replication. RR activity has been linked directly to the proliferation of normal and neoplastic cells, with significantly higher levels of RR activity being found in neoplastic cells (see E. Takeda and G. Weber, Life Sciences, 28, 1007 (1981) and G. Weber et al., Adv. Enz. Reg., 19, 87 (1981). Hence, the inhibition of RR activity is a valid target in the search for agents which will prevent or ameliorate abnormal cell proliferation as occurs, for example, in neoplasia and psoriasis.
Several inhibitors of mammalian RR have been investigated as potential antineoplastic agents or antitumor agents; for example, see B. van't Riet et al., J. Med. Chem., 22, 589 (1979), J. G. Cory et al., Adv. Enz. Reg., 19, 139 (1981), and B. van't Riet et al., U.S. Pat. No. 4,448,730, issued May 15, 1984. However, none have proved to be entirely satisfactory in clinical trials and only one RR inhibitor, hydroxyurea, is available to the physician for use as an antineoplastic agent. The latter drug, nevertheless, finds limited use because of side-effects and because frequent and large doses are required to maintain an effective concentration of the drug in vivo (see Van't Riet et al., J. Med. Chem., supra). Accordingly, there is a need for an effective and safe inhibitor of mammalian RR.
The present application discloses a new group of peptides which are potent inhibitors of mammalian RR. This attribute, together with a relative lack of toxicity, renders the peptides useful as agents for combatting disease states associated with abnormal cell proliferation.
Peptides have previously been reported to be inhibitors of RR, see for instance J. H. Subak-Sharpe et al., UK patent application 2185024, published July 8, 1987, E. A. Cohen et al., European patent application 246630, published Nov. 25, 1987, and R. Freidinger et al., European patent application 292255, published Nov. 23, 1988. However, unlike the present peptides, the previously reported peptides are inhibitors of a viral RR and not mammalian RR.